摘要
利用UPLC-MS/MS方法,建立大鼠血浆中千金子活性P-糖蛋白调控剂[Euphorbia factor L2(1)和3,5-dibenzoyl-15-hydroxylathyrol(2)]作用下多奈哌齐和美金刚的检测方法,进而考察两种P-糖蛋白调控剂对阿尔兹海默症药物的药代动力学影响.采用Agilent C-18(50 mm×2.1 mm,1.8μm),以乙腈∶水(5 mmol/L乙酸铵,0.2%甲酸)=70∶30为流动相,流速为0.2 mL/min,金刚烷胺为内标定量.通过优化制备条件、质谱参数、色谱参数,建立UPLC-MS/MS检测方法.将36只大鼠随机分为6组,仅灌胃给药多奈哌齐或美金刚组,先灌胃给药多奈哌齐或美金刚联合静脉注射1或2组,采用UPLC-MS/MS方法检测大鼠血药浓度并计算药代动力学参数.结果显示,多奈哌齐和美金刚分别在范围0.5-250 ng/mL和1.0-250 ng/mL中线性关系良好,方法学验证结果符合标准.药代动力学研究表明,多奈哌齐和美金刚在大鼠体内代谢受到P-糖蛋白调控剂影响.化合物1降低多奈哌齐的C_(max)、T_(max)、AUC_((0-t))和t_(1/2)的均值,升高CL/F,升高美金刚的C_(max)、T_(max)、AUC_((0-t))和t_(1/2)的均值,降低CL/F.化合物2使多奈哌齐和美金刚的T_(max)均值和AUC_((0-t))都升高,C_(max)都降低.上述结果为以P-糖蛋白调控剂为主要二次代谢产物,特别是以Lathyrane型二萜类似物为主要成分的药用植物与阿尔茨海默症药物相互作用的药代动力学研究提供了参考和方法基础.(图6表5参15)
This study aimed to establish an ultra-performance-tandem mass spectrometry(UPLC-MS/MS)method for the determination of donepezil and memantine in rat blood samples under the action of P-gp modulators(Euphorbia factor L_(2)(1)and 3,5-dibenzoyl-15-hydroxylathyrol(2)).As well,the pharmacokinetics of drugs for Alzheimer’s disease under the action of P-glycoprotein modulators was investigated.The analytes and the internal standard were separated with an Agilent C-18 column(50 mm×2.1 mm,1.8μm)by acetonitrile:water(5 mmol/L ammonium acetate,0.2%formic acid,70:30)as the mobile phase.The flow rate was 0.2 mL/min.Amantadine was the internal standard.The UPLC-MS/MS detection method was established by optimizing the preparation conditions,mass spectrometry parameters,and chromatographic parameters.Thirtysix rats were randomly divided into six groups.The control group was administered donepezil or memantine intragastrically.The experimental group was intragastrically administered donepezil or memantine,followed by the intravenous administration of 1 or 2.The blood concentration of rats was measured using UPLC-MS/MS,and the pharmacokinetic parameters were calculated.The calibration curves were linear in the range of 0.5-250 ng/mL and 1.0-250 ng/mL for donepezil and memantine,respectively.The methodological verification results met these criteria.Donepezil and memantine metabolism in rats was affected by P-glycoprotein modulators.Pharmacokinetic studies showed that the mean values of C_(max),T_(max),AUC_((0-t)),and t_(1/2) of donepezil were decreased by compound 1,and CL/F was increased.However,for memantine,the mean values of C_(max),T_(max),AUC_((0-t)),and t_(1/2) increased,and CL/F decreased.Trends for donepezil and memantine by compound 2 were nearly consistent.The mean values of T_(max) and AUC_((0-t))were increased by compound 2,and C_(max) decreased.The results provide a reference and methodological basis for the pharmacokinetic study of the interaction between medicinal plants with P-gp regulators as the main secondary metabolites and Alzheimer’s drugs,especially medicinal plants with lathyrane diterpene analogs as the main components.
作者
陈泳洁
李攀
向玲
杨春梅
张帆
焦威
CHEN Yongjie;LI Pan;XIANG Ling;YANG Chunmei;ZHANG Fan;JIAO Wei(School of Pharmacy,North Sichuan Medical College,Nanchong 637800,China;Natural Products Research Centre,Chengdu Institute of Biology,Chinese Academy of Sciences,Chengdu 610041,China;University of Chinese Academy of Sciences,Beijing 100049,China)
出处
《应用与环境生物学报》
CAS
CSCD
北大核心
2022年第2期372-378,共7页
Chinese Journal of Applied and Environmental Biology
基金
国家自然科学基金项目(21672205)
中国科学院“西部之光”基金项目(2017XBZG_XBQNXZ_A1_006)
中国科学院战略性生物资源服务网络项目(ZSTH-002)资助。
